Most solid tumors are epithelial in origin (i.e. carcinomas). A loss of epithelial cell markers (e.g. E-cadherin) and gain of mesenchymal cell markers (e.g. N-cadherin and Vimentin) has been observed in patient tumor samples, including prostate cancer (1). Cancer cells can dedifferentiate through this so-called Epithelial to Mesenchymal Transition (EMT). During EMT, intercellular cell junctions are broken down, thereby giving tumor cells the ability to migrate and invade into the surrounding tissue or through blood vessel walls. Such phenotypic changes are thought to play a major role in dissemination of the disease and ultimately lead to disease progression, which is often associated with poor prognosis for the patients (2;3).
Loss of E-cadherin expression is considered as a molecular hallmark of EMT. EMT in tumor cells results from a transcriptional reprogramming of the cell. In particular the transcriptional repression of the E-cadherin (CDH1) gene promoter has been shown to trigger the EMT phenotype. The E-cadherin protein is one of the most important cadherin molecules mediating cell-cell contacts in epithelial cells/tissues. CDH1 is repressed by binding of the transcriptional repressors, SNAI1, SNAI2, TCF3, TWIST, ZEB1, ZEB2 or KLF8 (4-7), to three so-called E-boxes in the CDH1 proximal promoter region (8-10). Inhibiting the binding of these repressors to the CDH1 promoter can revert EMT, also called mesenchymal to epithelial transition (MET), and inhibits tumor cell invasion and tumor progression (11).
Recently, the expression of several microRNAs has been shown to be linked with EMT (12). By comparing microRNA expression profiles of cells with an epithelial and (induced) mesenchymal phenotype, members of the miR-200 family (miR-141, miR-200a/b/c, and miR-429) and miR-205 were identified as EMT-associated miRs (13-15). The target genes of the EMT-associated microRNAs of the miR-200 family were shown to be ZEB1 and ZEB2. MicroRNAs targeting the other known transcriptional repressors of CDH1 (i.e. SNAI1, SNAI2, TCF3 and TWIST1) have not yet been found. The identification of these microRNAs in an expression profile of cells which have undergone EMT does not necessarily mean that these microRNAs are involved during EMT.
There is currently no effective known medicament that may be used for specifically preventing, treating, reverting and/or delaying a disease or condition associated with EMT in a subject. The only standard treatments comprise chemotherapy, radiotherapy, surgery. Particularly, the identification of patients that will or have already developed metastases and/or early treatment of patients with tumors expressing EMT markers, such as expression of mesenchymal Cadherin and/or lower expression of E-Cadherin could contribute to better disease free and overall survival. Therefore, there is still a need for diagnostic markers for EMT and for new treatments of disease or conditions associated with EMT.